We have demonstrated that an adult rat with a complete, mid-thoracic spinal cord transection can regain full weight-bearing stepping over a range of speeds, loads, and even directions when the spinal cord is stimulated tonically to increase the excitability of the lumbosacral locomotor circuitry. Furthermore, we learned that load- bearing sensory information can serve as the controller of these complex motor tasks and that the performance of these tasks can be improved even further with pharmacological and motor training interventions. Within the first 2.5 years of the present BRP Grant, not within the five years as initially proposed, we have gathered sufficient data to demonstrate that the human lumbosacral spinal cord has similar capabilities. We have shown that an individual with a motor complete spinal cord injury can regain independent standing, assisted stepping, and even a significant level of voluntary control of the lower limbs in the presence of epidural stimulation after months of testing different spinal cord stimulation patterns and motor training. Just as important and as impressive is the recovery of significant levels of bladder control, blood pressure, and temperature regulation, and even sexual function in this patient (13a). These intriguing results compel us to begin additional efforts to overcome what are now recognized as the most critical factors limiting our progress toward making this intervention available in the clinic. Based on our results, it is clear that we can develop the capability to selectively activae combinations of neural networks that can enable standing and probably stepping with improved technology in humans with a functionally motor complete spinal cord injury. These functional improvements are even more likely to benefit those individuals that are functionally motor incomplete, but have severely impaired mobility. Our present accomplishments have been realized using technology that is three decades old and initially designed for a different purpose, i.e., pain management. Thus we are requesting funds to overcome the present technical, not physiological, limitations as expediently and as carefully as possible. More specifically, the rat limiting factors are the lack of technology for chronic implants for a high number of electrodes and the need for a more clear understanding of how these epidural stimulation arrays can modulate the spinal circuitries. To overcome these factors we need to 1) develop a device that will allow us to chronically implant an integrated electrode array and multiplexed stimulation device in rats with the necessary signal control capabilities, 2) evaluate hypotheses that will guide us to more clearly understand how to modulate the stimulation parameters to activate the desired spinal circuits, 3) develop a learning strategy to automatically optimize the stimulation parameters for a given patient to stand, step, or exert voluntary control, and 4) begin to explore the pathways through which voluntary control can be regained after a severe spinal cord injury. PUBLIC HEALTH RELEVANCE: It now seems possible to develop a technology that will enable the recovery of postural and locomotor function in humans after a motor complete spinal cord injury. This technology includes the capability to stimulate the lower spinal cord in a manner that can enable a patient with complete paraplegia to stand and to step. This project outlines the newly recognized technical capabilities that must be developed to accomplish this goal.